tbuckley/cabot-search huggingface dataset:
Relevance of adjuvant chemotherapy in elderly patients with low rectal tumors.
Authors: Sola Adeleke, Aaron Davies, Somto Okoli, Kaiwen Wang, Nicholas Fraser Brown, Joao R Galante, Flora Elwes, Adrian Choy, Mariya Karova, Luna Dahal, Sneha George, Meeta Durve, Christos Mikropoulos, Albert Edwards, Rakesh Raman, Amanda Clarke
Journal: Journal of Clinical Oncology (2023)

37 Background: The balance between the benefits and toxicities of adjuvant systemic chemotherapy is crucial in the elderly, and often co-morbid patients who have undergone total mesorectal excision (TME) surgery for carcinomas of the lower rectum (1). Tumour distance from the anal verge is a known prognostic factor in rectal cancer (2, 3) and it may influence the effectiveness of adjuvant chemotherapy (AC) (4). This study evaluated the differences in the survival outcomes between patients on surveillance(S) and those who received AC in a multi-centre, real-world setting with a focus on the elderly cohort. Methods: Data was extracted from electronic patient records from 4 NHS trusts in Kent, UK. We retrospectively analysed records of patients between 1 Jan 2014 and 31 Dec 2019, who had neoadjuvant chemoradiotherapy, were down-staged and then offered either S or AC based on clinician’s judgement. The tumour distance from the anal verge was measured through high resolution MRI. The patients were downstaged following assessment as their pTNM staging was lower than their cTNM staging. Results: 589 patients treated for rectal cancer were identified. Of these, 168/589(28%) had non-metastatic disease, were later down-staged at TME and were offered S or AC. 95/168 (57%) of these patients received AC. Patients who received AC were younger (median age 63 vs 70 years, p&lt; 0.001) and with additional poor prognostic factors such as extramural venous invasion EMVI+ (74 vs 39%, p= 0.001), circumferential resection margin CRM+ (89 vs 70% p = 0.001) and pathological nodal involvement (AJCC stage III disease) ( p&lt; 0.001) (table) compared to those on S. Our findings did suggest that patients on surveillance with tumours &lt; 5cm from the anal verge had a longer disease-free survival(DFS) than those who received chemotherapy; this was especially the case in the elderly patient cohort (HR 0.13 95% CI 0.02-0.99, p= 0.049).Our findings also showed that the DFS benefit for patients under surveillance increased with age. Surveillance was most effective in patients over 60 years old compared to those under 60. However, age or distance from anal verge did not have an impact on overall survival (HR 1.01 95% Cl 0.95-1.08 p= 0.70). Conclusions: Although patients treated with AC were younger than patients on S, their tumours had additional poor prognostic factors. Patients on surveillance with tumours &lt;5cm from the anal verge enjoyed a longer DFS but no OS benefit. Elderly patients with tumours &lt; 5cm from the anal verge with no poor prognostic features could derive a benefit from surveillance and avoid chemotherapy-related toxicity. However, our findings will need to be corroborated in prospective studies. [Table: see text]
Patient-reported outcomes (PROs) and biomarker assessments in daNIS-3, a phase II platform study of NIS793 (anti–TGF-β monoclonal antibody) and other investigational drug combinations with standard of care (SOC) vs SOC alone in patients (pts) with second-line metastatic colorectal cancer (mCRC).
Authors: Scott Kopetz, Stefan Kasper, Fernando Rivera, Christophe Tournigand, Yuan Cheng, Priya Deshpande, Denise D'Alessio, Nabil Amirouchene Angelozzi, Ana Bento Pereira da Silva, Neil Howard Segal
Journal: Journal of Clinical Oncology (2023)

TPS272 Background: Despite the utilization of systemic targeted agents with chemotherapy for mCRC, long-term survival remains poor. Disease progression in mCRC is common, and SOC options are associated with reduced quality of life (QoL) that has been negatively associated with survival. Here, we present daNIS-3, a Phase II, randomized, open-label platform study (NCT04952753) of NIS793 and other investigational drug combinations in pts with second-line mCRC, with an emphasis on the exploratory PROs and biomarker assessments. Methods: Eligible pts are adults with microsatellite-stable mCRC who have progressed on or within 6 months of one prior line of systemic therapy for mCRC and are not amenable to potentially curative surgery. Pts are treated with NIS793 (Day [D]1 ± D15; 2100 mg) + SOC (D1 + D15; bevacizumab [5 mg/kg] + FOLFIRI/mFOLFOX6) +/- tislelizumab (D1; 300 mg), or SOC alone. All drugs are administered intravenously on 28-day cycles. Each investigational arm begins with a safety run-in involving ≥6 eligible pts; safety run-in of the tislelizumab arm follows completion of the NIS793 + SOC safety run-in. Following confirmation of the recommended dose, pts are randomized (2:1) in the expansion part to receive investigational drug(s) + SOC (n≈75) or SOC alone (n≈38). Exploratory objectives include PROs (expansion part only) and biomarker assessments. PRO measures (EORTC-QLQ-C30, QLQ-CR29, PRO-CTCAE, and FACT-GP5) will be collected electronically throughout the study and used to explore pt-reported disease symptoms, health-related QoL, functioning, and treatment-related side effects. Potential biomarkers of response and mechanisms of resistance will be assessed in tumor and blood samples. Baseline archival/tumor biopsies will be collected to assess the correlations between clinical response and molecular subtype, tumor mutational burden, TGF-β gene signatures, and immune-related biomarkers. Optional biopsies during Cycle 3 and at the end of treatment will be used to assess pharmacodynamic effects of NIS793 on the tumor microenvironment and resistance mechanisms, respectively. Circulating tumor DNA and cytokine and TGF-β levels will be continuously monitored through serial blood samples to evaluate treatment benefit, correlate alterations with response, and assess the effect(s) of NIS793. An additional blood sample for nucleic acid analysis will evaluate the effect(s) of TGF-β blockade. The daNIS-3 study started on November 15, 2021, and plans to recruit approximately 266 pts from 77 sites across 19 countries. Clinical trial information: NCT04952753 .
The real-world prevalence of esophagogastric varices, bleeding, emergency room visits, and hospitalization among patients with advanced hepatocellular carcinoma in the US.
Authors: Neehar Parikh, Shengsheng Yu, Noh Jin Park, Michael Locker, Ishveen Chopra, Jason Yeaw
Journal: Journal of Clinical Oncology (2023)

519 Background: Upper gastrointestinal bleeding associated with esophagogastric varices (EGV) is a morbid and potentially deadly complication of advanced hepatocellular carcinoma (aHCC). However, the presence of EGV among the aHCC population receiving esophagogastroduodenoscopy (EGD) in the US is not well understood, nor are the predictors of EGV- or bleeding-related ER or hospitalization (the outcome) among those who are newly initiated on systemic treatment. Methods: A retrospective cohort analysis was conducted utilizing IQVIA’s PharMetrics Plus Health Plans Claims database (January 1, 2016, to July 31, 2021). Patients ≥18 years of age with ≥1 prescription for an aHCC systemic treatment were included; the date of the first prescription was the index date. At least 12 months of continuous enrollment pre-index and 6 months post-index (unless patients were deceased) were required. Patients with pre-index diagnosis codes for renal cell carcinoma, differentiated thyroid carcinoma, colorectal cancer, gastric cancer, non-small cell lung carcinoma, and liver transplant were excluded. Logistic regression was conducted to identify associations between baseline characteristics and the outcome. Results: A total of 904 patients with aHCC were included (mean age: 61.3 years; 75.3% male); 39.4% of patients died within 6 months following the index date. During the pre-index period, 688 (76.1%) patients had portal hypertension-related comorbidity, 327 (36.2%) had EGD, 122 (13.5%) had EGV, and 63 (7.0%) had bleeding. During the observational period, 458 (50.7%) patients received EGD, among whom 209 (45.6%) also had EGV. 141 (15.6%) patients had ≥1 outcome event during the post-index period. In the adjusted analysis, patients with pre-index bleeding and with EGV but no bleeding had 4.5- and 3.1-times higher odds of having post-index outcome, respectively, as compared with those lacking pre-index bleeding and EGV. Moreover, the pre-index presence of portal hypertension-related comorbidities was associated with 3.1 times greater odds of having a post-index outcome. Conclusions: EGV and bleeding events are common in patients with aHCC receiving systemic therapies. The EGV prevalence of 45.6% among those receiving EGD is consistent with prior similar studies outside of the US (Giannini EG, et al. Clin Gastroenterol and Hepatol. 2006; Iavarone M, et al. United European Gastroenterol J. 2016; Hsieh WY, et al. Sci Rep. 2017). The presence of bleeding, EGV, and portal hypertension-related comorbidities prior to treatment initiation were associated with the increased post-treatment risk of EGV- or bleeding-related ER or hospitalization in these patients. To our knowledge, this is the first study to assess and report the presence of EGV among those receiving EGD in a US aHCC population.
Development of a Magnetic Resonance Imaging–Based Definition of Knee Osteoarthritis: Data From the Multicenter Osteoarthritis Study
Authors: Jean W. Liew, Gabriela Rabasa, Michael LaValley, Jamie Collins, Joshua Stefanik, Frank W. Roemer, Ali Guermazi, Cora E. Lewis, Michael Nevitt, James Torner, David Felson
Journal: Arthritis & Rheumatology (2023)

Objective Although magnetic resonance imaging (MRI) is the imaging modality of choice for research, there is no widely accepted MRI definition of knee osteoarthritis (OA). We undertook this study to test the performance of different MRI definitions of OA. Methods We studied Multicenter Osteoarthritis Study participants with knee symptoms using posteroanterior and lateral knee radiographs and MRIs. Radiographic OA was defined as Kellgren/Lawrence grade ≥2 in the tibiofemoral (TF) and/or patellofemoral (PF) joint. Symptomatic OA was defined using a validated questionnaire. MRI findings of cartilage damage, osteophytes, bone marrow lesions (BMLs), and synovitis were scored using the Whole‐Organ MRI Score system. We compared definitions using combinations of MRI features to the validation criteria of prevalent radiographic OA and symptomatic OA. All combinations included cartilage damage score ≥2 (0–6 scale) and osteophyte score ≥2 (0–6 scale); addition of BMLs and synovitis score was also tested. We also evaluated a Delphi panel definition that defined OA differently for the PF and TF joints. For each definition, we calculated sensitivity, specificity, and the area under the curve (AUC). Results We included 1,185 knees from 1,185 participants (mean age 66 years, 62% female, 89% White). Among the 1,185 knees, 482 knees had radiographic OA, and 524 knees had symptomatic OA. The MRI definitions with a cartilage score ≥2 and osteophyte score ≥2 and definitions which added BMLs or synovitis score ≥1 had the highest sensitivities (95.2% and 94.5%, respectively) for prevalent radiographic OA (AUCs 0.67 and 0.69, respectively), and also had the highest sensitivities for symptomatic OA. The Delphi panel definition had similar performance but was more complex to apply. Conclusion An MRI OA definition requiring cartilage damage and a small osteophyte with or without BMLs or synovitis had the best performance and was simplest for identifying radiographic OA and symptomatic OA.
Simple Aspiration versus Drainage for Complete Pneumothorax: A Randomized Noninferiority Trial
Authors: Tania Marx, Luc-Marie Joly, Anne-Laure Parmentier, Jean-Baptiste Pretalli, Marc Puyraveau, Jean-Claude Meurice, Jeannot Schmidt, Olivier Tiffet, Gilbert Ferretti, Dominique Lauque, Didier Honnart, Faraj Al Freijat, Alain Eric Dubart, Romain Genre Grandpierre, Alain Viallon, Dominique Perdu, Pierre Marie Roy, Toufiq El Cadi, Nathalie Bronet, Grégory Duncan, Gilles Cardot, Philippe Lestavel, Frédéric Mauny, Thibaut Desmettre
Journal: American Journal of Respiratory and Critical Care Medicine (2023)

Rationale: Management of first episodes of primary spontaneous pneumothorax remains the subject of debate. Objectives: To determine whether first-line simple aspiration is noninferior to first-line chest tube drainage for lung expansion in patients with complete primary spontaneous pneumothorax. Methods: We conducted a prospective, open-label, randomized noninferiority trial. Adults aged 18-50 years with complete primary spontaneous pneumothorax (total separation of the lung from the chest wall), recruited at 31 French hospitals from 2009 to 2015, received simple aspiration (n = 200) or chest tube drainage (n = 202) as first-line treatment. The primary outcome was pulmonary expansion 24 hours after the procedure. Secondary outcomes were tolerance of treatment, occurrence of adverse events, and recurrence of pneumothorax within 1 year. Substantial discordance in the numerical inputs used for trial planning and the actual trial rates of the primary outcome resulted in a reevaluation of the trial analysis plan. Measurement and Main Results: Treatment failure occurred in 29% in the aspiration group and 18% in the chest tube drainage group (difference in failure rate, 0.113; 95% confidence interval [CI], 0.026-0.200). The aspiration group experienced less pain overall (mean difference, -1.4; 95% CI, -1.89, -0.91), less pain limiting breathing (frequency difference, -0.18; 95% CI, -0.27, -0.09), and less kinking of the device (frequency difference, -0.05; 95% CI, -0.09, -0.01). Recurrence of pneumothorax was 20% in this group versus 27% in the drainage group (frequency difference, -0.07; 95% CI, -0.16, +0.02). Conclusions: First-line management of complete primary spontaneous pneumothorax with simple aspiration had a higher failure rate than chest tube drainage but was better tolerated with fewer adverse events. Clinical trial registered with www.clinicaltrials.gov (NCT01008228).
Year-round longitudinal health surveillance in UK Olympic Summer Sport Athletes 2016–2019
Authors: Craig Ranson, Moses Wootten, Anita Biswas, Lee Herrington, David Gallimore, Paul D Jackson, Abbie Taylor, Simon Spencer, James Hull, Steve McCaig
Journal: British Journal of Sports Medicine (2023)

To identify the priority injury and illness types across UK summer Olympic World Class Programme sports to inform development, implementation and evaluation of associated injury risk mitigation and management initiatives.Four years (2016-2019) of electronic medical records of 1247 athletes from 22 sports were analysed and reported using methods based on the 2020 International Olympic Committee consensus statement for epidemiological recording and reporting.3562 injuries and 1218 illness were recorded, accounting for 146 156 and 27 442 time-loss days. Overall, 814 (65%) athletes reported at least one injury, while 517 (41%) reported at least one illness. There were 1.3 injuries per athlete year resulting in a mean burden of 54.1 days per athlete year. The lumbar/pelvis, knee, ankle and shoulder body regions had the highest incidence and burden. Athletes reported 0.5 illnesses per athlete year, resulting in a mean burden of 10.4 days per athlete year, with most composed of respiratory illness and gastroenteritis. Injuries within sport groups were representative of the injury risk profile for those sports (eg, knee, hand and head injuries had the highest incidence in combat sports), but respiratory illnesses were consistently the greatest problem for each sport group.To optimise availability for training and performance, systematic risk mitigation and management initiatives should target priority injury problems occurring in the lumbar/pelvis, knee, ankle and shoulder, and respiratory illness. Follow-up analysis should include identification of sport-specific priority health problems and associated risk factors.
CD28-CAR-T cell activation through FYN kinase signaling rather than LCK enhances therapeutic performance
Authors: Ling Wu, Joanna Brzostek, Previtha Dawn Sakthi Vale, Qianru Wei, Clara K.T. Koh, June Xu Hui Ong, Liang-zhe Wu, Jia Chi Tan, Yen Leong Chua, Jiawei Yap, Yuan Song, Vivian Jia Yi Tan, Triscilla Y.Y. Tan, Junyun Lai, Paul A. MacAry, Nicholas R.J. Gascoigne
Journal: Cell Reports Medicine (2023)

Signal transduction induced by chimeric antigen receptors (CARs) is generally believed to rely on the activity of the SRC family kinase (SFK) LCK, as is the case with T cell receptor (TCR) signaling. Here, we show that CAR signaling occurs in the absence of LCK. This LCK-independent signaling requires the related SFK FYN and a CD28 intracellular domain within the CAR. LCK-deficient CAR-T cells are strongly signaled through CAR and have better in vivo efficacy with reduced exhaustion phenotype and enhanced induction of memory and proliferation. These distinctions can be attributed to the fact that FYN signaling tends to promote proliferation and survival, whereas LCK signaling promotes strong signaling that tends to lead to exhaustion. This non-canonical signaling of CAR-T cells provides insight into the initiation of both TCR and CAR signaling and has important clinical implications for improvement of CAR function.
Advisory Board and Contents
Authors: Xu Zhang, Fabricio Do, Dmitri Rusakov, Matthew Davenport, Erich Jarvis, Jaan Aru, Moritz Drüke, Juhan Pikamäe, Matthew Larkum, Marcela Lipovsek, Ana Elgoyhen, Kei Igarashi, Jack Collier, Monika Oláhová, Thomas Mcwilliams, Robert Taylor, Manu Sharma, Jacqueline Burré, Moran Furman, Danielle Loughlin, Fred Kop, Patrick Scheffmann, Silvia Arber, Emery Brown, Rui Costa, Ann Craig, John Cryan, Catherine Dulac, Yukiko Goda, Kenneth Harris, Nancy Ip, Meyer Jackson, Maria Karayiorgou, Nancy Kopell, Robert Malenka, Mark Mattson, Freda Miller, Richard Morris, Maiken Nedergaard, Eric Nestler, Kia Nobre, Marco Prinz, Anna Wang, Roe Carmen, Sandi Klaas, Enno Stephan, Greg Stuart, Christopher Walsh, Xiaoqin Wang
Journal: Trends in Neurosciences (2023)
TYRO3 blockade enhances anti-PD-1 therapy response by modulating expression of CCN1 in tumor microenvironment
Authors: Miso Park, Da-Sol Kuen, Jaewoo Park, Munkyung Choi, Yeonji Kim, Eun Chae Roh, Yong June Choi, Yoon Gyoon Kim, Yeonseok Chung, Sung Yun Cho, Keon Wook Kang
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background Immunological contexture differs across malignancies, and understanding it in the tumor microenvironment (TME) is essential for development of new anticancer agents in order to achieve synergistic effects with anti-programmed cell death protein-1 (PD-1) therapy. TYRO3, AXL, and MERTK receptors are bi-expressed in both cancer and immune cells, and thus emerge as promising targets for therapeutic intervention. Whereas AXL and MERTK have been extensively studied, the role of TYRO3, in the TME, is still undetermined. Methods Here, we screened the TYRO3-focused chemical library consisting of 208 compounds and presented a potent and highly selective TYRO3 inhibitor, KRCT87. We explored the role of TYRO3 using mouse engrafting MC38 or 4T1 tumors. We validated the results using flow cytometry, RNA sequencing analysis, gene knockdown or overexpression, ex vivo immune cells isolation from mouse models, immunoblotting and quantitative PCR. Flow cytometry was used for the quantification of cell populations and immunophenotyping of macrophages and T cells. Co-cultures of macrophages and T cells were performed to verify the role of CCN1 in the tumors. Results TYRO3 blockade boosts antitumor immune responses in both the tumor-draining lymph nodes and tumors in MC38-syngeneic mice models. Moreover, the combination of KRCT87 and anti-PD-1 therapy exerts significant synergistic antitumor effects in anti-PD-1-non-responsive 4T1-syngeneic model. Mechanistically, we demonstrated that inhibition of TYRO3-driven CCN1 secretion fosters macrophages into M1-skewing phenotypes, thereby triggering antitumor T-cell responses. CCN1 overexpression in MC38 tumors diminishes responsiveness to anti-PD-1 therapy. Conclusions The activated TYRO3-CCN1 axis in cancer could dampen anti-PD-1 therapy responses. These findings highlight the potential of TYRO3 blockade to improve the clinical outcomes of anti-PD-1 therapy.
Cerebral regional tissue Oxygen Saturation to Guide Oxygen Delivery in preterm neonates during immediate transition after birth (COSGOD III): multicentre randomised phase 3 clinical trial
Authors: Gerhard Pichler, Katharina Goeral, Marlene Hammerl, Tina Perme, Eugene M Dempsey, Laila Springer, Gianluca Lista, Tomasz Szczapa, Hans Fuchs, Lukasz Karpinski, Jenny Bua, Alexander Avian, Brenda Law, Berndt Urlesberger, Julia Buchmayer, Ursula Kiechl-Kohlendorfer, Lilijana Kornhauser-Cerar, Christoph E Schwarz, Kerstin Gründler, Ilaria Stucchi, Bernhard Schwaberger, Katrin Klebermass-Schrehof, Georg M Schmölzer
Journal: BMJ (2023)

Abstract Objective To investigate whether monitoring of cerebral tissue oxygen saturation using near infrared spectroscopy in addition to routine monitoring combined with defined treatment guidelines during immediate transition and resuscitation increases survival without cerebral injury of premature infants compared with standard care alone. Design Multicentre, multinational, randomised controlled phase 3 trial. Setting 11 tertiary neonatal intensive care units in six countries in Europe and in Canada. Participants 1121 pregnant women (&lt;32 weeks’ gestation) were screened prenatally. The primary outcome was analysed in 607 of 655 randomised preterm neonates: 304 neonates in the near infrared spectroscopy group and 303 in the control group. Intervention Preterm neonates were randomly assigned to either standard care (control group) or standard care plus monitoring of cerebral oxygen saturation with a dedicated treatment guideline (near infrared spectroscopy group) during immediate transition (first 15 minutes after birth) and resuscitation. Main outcome measure The primary outcome, assessed using all cause mortality and serial cerebral ultrasonography, was a composite of survival without cerebral injury. Cerebral injury was defined as any intraventricular haemorrhage or cystic periventricular leukomalacia, or both, at term equivalent age or before discharge. Results Cerebral tissue oxygen saturation was similar in both groups. 252 (82.9%) out of 304 neonates (median gestational age 28.9 (interquartile range 26.9-30.6) weeks) in the near infrared spectroscopy group survived without cerebral injury compared with 238 (78.5%) out of 303 neonates (28.6 (26.6-30.6) weeks) in the control group (relative risk 1.06, 95% confidence interval 0.98 to 1.14). 28 neonates died (near infrared spectroscopy group 12 (4.0%) v control group 16 (5.3%): relative risk 0.75 (0.33 to 1.70). Conclusion Monitoring of cerebral tissue oxygen saturation in combination with dedicated interventions in preterm neonates (&lt;32 weeks’ gestation) during immediate transition and resuscitation after birth did not result in substantially higher survival without cerebral injury compared with standard care alone. Survival without cerebral injury increased by 4.3% but was not statistically significant. Trial registration ClinicalTrials.gov NCT03166722 .
Wearable Hydrogel‐Based Epidermal Sensor with Thermal Compatibility and Long Term Stability for Smart Colorimetric Multi‐Signals Monitoring (Adv. Healthcare Mater. 3/2023)
Authors: Fei Han, Xueyong Xie, Tiansong Wang, Chaoyu Cao, Juju Li, Tianying Sun, Hao Liu, Songmei Geng, Zhao Wei, Jing Li, Feng Xu
Journal: Advanced Healthcare Materials (2023)

Wearable Sensors In article number 2201730 by Feng Xu and co-workers, freestanding smart colorimetric hydrogel-based wearable epidermal sensors are utilized for simultaneously monitoring the pH, temperature, and light, where colorimetric signals can be read and stored by artificial intelligence strategies in a real-time manner. This developed wearable transparent epidermal sensor holds great potential for monitoring multi-signals with visible readouts in long-term health monitoring.